Abrogation of Pancreatic Cancer Using a Brain Malady Drug

Abstract

Pancreatic cancer is the fourth preeminent cause of cancer-related deaths with a poor prognosis. Desmoplasia and drug resistance are few of the pivotal hurdles in pancreatic cancer management. Unlike breast cancer, awareness about pancreatic cancer still lacks in all the aspects. Our extensive bioinformatic and clinical data mining led us to notice an abnormal upregulation of a membrane protein Sphingosine-1-Phosphate Receptor-1 (S1PR1) in pancreatic cancer. S1PR1 is an important lipid signalling receptor whose ligand is a bioactive lipid, Sphingosine-1-phosphate. We were curious to know what happens to the cancer cell if we block this active lipid signaling. So, we targeted this protein using its antagonist, FTY720, which is already in the market for a known brain disorder called multiple sclerosis. FDA accreditation and known ADMET patters prompted us to choose this pre-existing drug. Accordingly, time-consuming clinical trials could be bypassed leading to rapid repurposing for pancreatic cancer. Our in vitro studies on numerous pancreatic cancer cell lines displayed a dose-dependent increase in cell death with low toxicity on normal cells. Although, gemcitabine is the first line chemotherapeutic drug for pancreatic cancer, the emergence of resistance among the patients was observed which leads to metastasis. In particular, combination therapy is an imminent approach to tackle the trouble of drug resistance. Indeed, an amalgamation of FTY720 and gemcitabine showed the enhanced anticancer effects on ex vivo experiments. Furthermore, two animal models showed the conspicuous abatement in tumor chunk as a result of blended drug treatment for 30 days. Besides, reduction of significant cell proliferation markers in the tumor microenvironment was observed. We found that FTY720 alone and also in commixture with gemcitabine effectively ameliorated the activity of PP2A which is the known target of FTY720. STAT3 is a transcription factor, which plays a remarkable role in carcinogenesis. We also observed a reduced S1PR1-STAT3 loop in vivo along with its downstream survival proteins due to strong affinity of FTY720 on the S1PR1 receptor. Since the combination of FTY720+Gem showed an astonishing role in abatement of tumor size than solitary treatment, the exact role of this combination strategy was explained by exploring the role of FTY720, which may act as a trooper for gemcitabine to cross the desmoplasia, an enlarged collagen area. As expected, we found a reduction in desmoplastic markers in the FTY720 treatment group. It infers that FTY720 loosens up the tumor tissue so that gemcitabine can readily reach the cancer cells. In conclusion, we propose that FTY720 can be a propitious molecule in pancreatic cancer management in combination with other chemotherapeutic drugs. Support or Funding Information University Grants Commision, Government of India and Department of Biotechnology, Government of India. The Mechanism of action of the combination therapy in pancreatic cancer. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.